Gestational diabetes prevention and treatment: a protocol for developing core outcome sets

Introduction: Selective reporting bias, inconsistency in the chosen outcomes between trials and irrelevance of the chosen outcomes for women, limit the efficiency and value of research for prevention and treatment of gestational diabetes mellitus (GDM). One way to address these challenges is to develop core outcome sets (COSs). Methods and analysis: The aim of this manuscript is to present a protocol for a study to develop COSs for GDM prevention and treatment. This is a three-phase project consisting of (1) a systematic review of the literature to create two lists of outcomes that have been reported in trials and systematic reviews of trials of interventions for the prevention and treatment of GDM, (2) a three-round, web-based e-Delphi survey with key stakeholders to prioritise these outcomes and (3) a consensus meeting to resolve any remaining disagreements and to agree on two COSs. Ethics and dissemination: Ethical approval to conduct this study was obtained from the ethics committee at Galway University Hospitals on 13 December 2018 (Reference: C.A.2078). We will disseminate our research findings through peer-reviewed, open access publications and present at international conferences to reach a wide range of knowledge users

A core outcome set for studies of gestational diabetes mellitus prevention and treatment

AIMS/HYPOTHESIS: The aim of this systematic review was to develop core outcome sets (COSs) for trials evaluating interventions for the prevention or treatment of gestational diabetes mellitus (GDM). METHODS: We identified previously reported outcomes through a systematic review of the literature. These outcomes were presented to key stakeholders (including patient representatives, researchers and clinicians) for prioritisation using a three-round, e-Delphi study. A priori consensus criteria informed which outcomes were brought forward for discussion at a face-to-face consensus meeting where the COS was finalised. RESULTS: Our review identified 74 GDM prevention and 116 GDM treatment outcomes, which were presented to stakeholders in round 1 of the e-Delphi study. Round 1 was completed by 173 stakeholders, 70% (121/173) of whom went on to complete round 2; 84% (102/121) of round 2 responders completed round 3. Twenty-two GDM prevention outcomes and 30 GDM treatment outcomes were discussed at the consensus meeting. Owing to significant overlap between included prevention and treatment outcomes, consensus meeting stakeholders agreed to develop a single prevention/treatment COS. Fourteen outcomes were included in the final COS. These consisted of six maternal outcomes (GDM diagnosis, adherence to the intervention, hypertensive disorders of pregnancy, requirement and type of pharmacological therapy for hyperglycaemia, gestational weight gain and mode of birth) and eight neonatal outcomes (birthweight, large for gestational age, small for gestational age, gestational age at birth, preterm birth, neonatal hypoglycaemia, neonatal death and stillbirth). CONCLUSIONS/INTERPRETATION: This COS will enable future GDM prevention and treatment trials to measure similar outcomes that matter to stakeholders and facilitate comparison and combination of these studies. TRIAL REGISTRATION: This study was registered prospectively with the Core Outcome Measures in Effectiveness Trials (COMET) database: http://www.comet-initiative.org/studies/details/686/

Accelerated metabolism of nicotine and cotinine in pregnant smokers. J Pharmacol Exp Ther 2002; 301: 594–598

ABSTRACT Cigarette smoking is the foremost modifiable risk factor for adverse pregnancy outcomes. Nicotine is a suspected fetal neuroteratogen. There is concern that nicotine may achieve toxic levels during pregnancy if nicotine replacement therapies are prescribed at doses used in the nonpregnant state. Ten healthy, volunteer, pregnant smokers received infusions of deuterium-labeled nicotine and cotinine during pregnancy and again postpartum. From blood and urine measurements, the following were determined: clearance (renal and nonrenal) of nicotine and cotinine, clearance of nicotine via the cotinine pathway (an indicator of CYP2A6 activity), and daily intake of nicotine from smoking. The clearance of nicotine and cotinine was significantly higher (60 and 140%, respectively), and the half-life of cotinine was much shorter (8.8 versus 16.6 h, P Ͻ 0.01) during pregnancy. Although plasma levels of cotinine were lower during pregnancy (119 versus 202 ng/ml, P Ͻ 0.05), daily intake of nicotine from smoking was similar during pregnancy and postpartum. For a given level of intake, the pharmacologic and toxicologic effects of nicotine during pregnancy are anticipated to be less than expected from nicotine metabolism data in nonpregnant women. Our data indicate that no downward dose adjustment needs to be made for nicotine replacement therapy during pregnancy. Conversely, higher than usual doses of nicotine may be necessary to optimize efficacy. Lower cotinine levels observed during pregnancy do not necessarily reflect less smoke exposure, and cut-off levels used to classify nonsmokers, passive smokers, and active smokers need to be established for pregnancy

Genetic and pharmacokinetic determinants of response to transdermal nicotine in white, black, and Asian nonsmokers

The aim of the study was to examine genetic, pharmacokinetic, and demographic factors that influence sensitivity to nicotine in never-smokers. Sixty never-smokers, balanced for gender and race (white, black, and Asian), wore 7-mg nicotine skin patches fo

Genetic and pharmacokinetic determinants of response to transdermal nicotine in white, black, and Asian nonsmokers

The aim of the study was to examine genetic, pharmacokinetic, and demographic factors that influence sensitivity to nicotine in never-smokers. Sixty never-smokers, balanced for gender and race (white, black, and Asian), wore 7-mg nicotine skin patches fo

Butanediol conversion to gamma-hydroxybutyrate markedly reduced by the alcohol dehydrogenase blocker fomepizole.

1,4-Butanediol (BDO) - used as solvent, and abused for its euphoric effects - is converted to gamma-hydroxybutyrate (GHB) by the enzyme alcohol dehydrogenase (ADH). This double-blind, placebo-controlled crossover study with six healthy volunteers is the first to date investigating the role of the ADH inhibitor fomepizole (4MP) in moderating this conversion in humans. Participants received on two different days either intravenous placebo or 15 mg/kg 4MP, followed by oral administration of 25 mg/kg BDO. Pretreatment with 4MP resulted in significantly higher BDO maximal plasma concentration (p=0.001) and AUC (p=0.028), confirming that ADH is the primary pathway for the conversion of BDO to GHB in humans. With 4MP, the mean arterial pressure was significantly lower at 105 minutes compared to baseline (p=0.003), indicating that blood pressure lowering, observed not with a temporal relationship to 4MP administration but after the maximum BDO concentration was reached, may be an intrinsic effect of BDO. This article is protected by copyright. All rights reserved

The influence of nicotine metabolic rate on working memory over 6 hours of abstinence from nicotine.

BACKGROUND: A faster rate of nicotine metabolism has been associated with smoking more cigarettes, greater nicotine withdrawal symptoms, and lower smoking quit rates. However, the association between nicotine metabolic rate (NMR) and cognitive functioning during withdrawal has not been determined. METHODS: We compared cognitive function in 121 fast or slow nicotine metabolizers after smoking, and at 3 and 6 h of nicotine abstinence. Cognitive functioning was assessed using N-back working memory tests with outcomes of accuracy and processing speed. Participants smoked two cigarettes and then abstained from smoking for 6 h. N-back tests were administered after smoking (0 h) and at 3 and 6 h of nicotine abstinence. RESULTS: An effect of processing speed was found over time on the 2-back, in that participants had significantly longer average reaction times when the stimuli presented did not match the target letter. NMR was not significantly associated with the processing speed change over time. Within-race differences in working memory were evident in that Caucasian fast metabolizers had significantly poorer accuracy and processing speed. CONCLUSIONS: Minimal change in working memory over 6 h of nicotine abstinence was observed. Overall, NMR was not significantly associated with the change in processing speed, however Caucasian fast metabolizers displayed poorer accuracy and processing speed at discrete time points

CYP2A6 genotype but not age determines cotinine half-life in infants and children

The formation of cotinine, the main proximate metabolite and a biomarker of nicotine exposure, is mediated primarily by cytochrome P450 (CYP)2A6. Our aim was to determine whether higher cotinine levels in young children exposed to secondhand smoke (SHS) a